Homocysteine and Coronary Artery Disease With special Reference to Biochemical Effects Of Vitamin Therapy

Sammanfattning: An elevated plasma level of homocysteine has been suggested as a risk factor for cardiovascular disease. The objectives of this thesis were to study the influence of renal function on homocysteine levels in patients with coronary artery disease and to explore the association of elevated plasma levels of homocysteine to oxidative stress, inflammation, and endothelial dysfunction. The effects of plasma homocysteine lowering with vitamin supplementation were also studied. Paper 1. Patients with coronary heart disease were studied, 59 with elevated levels of plasma homocysteine and 34 with low-normal levels. Patients with elevated levels had higher serum concentrations of cystatin C, a marker for glomerular filtration rate, than patients with low-normal levels of homocysteine. However, a large overlap in cystatin C concentrations between these two groups of patients, suggested that subtle renal dysfunction is not a major determinant of high plasma concentrations of homocysteine in patients with coronary artery disease. Paper 2 . The main findings of this study were that patients with coronary artery disease and high plasma homocysteine had a lowered ratio of reduced to total homocysteine in plasma, which might reflect increased oxidative activity or decreased reducing capacity in plasma. Vitamin therapy normalised the plasma homocysteine concentrations but the redox status remained unchanged. Paper 3. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, was not increased in patients with coronary artery disease and high plasma concentration of homocysteine. Substantial reduction of homocysteine by vitamin supplementation did not affect the level of plasma ADMA. Paper 4. Patients with coronary artery disease and high plasma homocysteine levels had elevated levels of isoprostanes, markers of lipid peroxidation. The increase remained unaffected by plasma homocysteine-lowering therapy, suggesting that homocysteine per se does not cause increased lipid peroxidation. Two out of eight inflammatory markers studied were increased in patients with high plasma homocysteine levels compared to patients with low-normal levels, suggesting an association between homocysteinemia and low-grade inflammation. Paper 5. We investigated 334 consecutive patients with acute coronary syndrome. Plasma homocysteine levels correlated with markers of inflammation (C reactive protein (CRP) and orosomucoid) but not with levels of antibodies against LDL. In conclusion, increased lipid peroxidation and altered redox status in patients with hyperhomocysteinemia do not appear to be caused by homocysteine itself. Elevated plasma homocysteine does not increase plasma levels of ADMA. Hyperhomocysteinemia is linked to an inflammatory reaction.